PAHO (2019) Guidelines for the diagnosis and treatment of Chagas disease. https://www.who.int/publications-detail-redirect/9789275120439. Accessed 24 Jun 2022

Malone CJ, Nevis I, Fernández E, Sanchez A (2021) A Rapid Review on the efficacy and safety of pharmacological treatments for Chagas Disease. Trop Med Infect Dis 6:128. https://doi.org/10.3390/tropicalmed6030128

Article  Google Scholar 

Pérez-Molina JA, Crespillo-Andújar C, Bosch-Nicolau P, Molina I (2020) Trypanocidal treatment of Chagas disease. Enfermedades Infecc Microbiol Clin Engl Ed. https://doi.org/10.1016/j.eimc.2020.04.011

Article  Google Scholar 

Carrillo C, Canepa GE, Algranati ID, Pereira CA (2006) Molecular and functional characterization of a spermidine transporter (TcPAT12) from Trypanosoma cruzi. Biochem Biophys Res Commun 344:936–940. https://doi.org/10.1016/j.bbrc.2006.03.215

Article  Google Scholar 

Carrillo C, Cejas S, Huber A et al (2003) Lack of arginine decarboxylase in Trypanosoma cruzi epimastigotes. J Eukaryot Microbiol 50:312–316. https://doi.org/10.1111/j.1550-7408.2003.tb00141.x

Article  Google Scholar 

Michael AJ (2016) Polyamines in eukaryotes, bacteria, and archaea. J Biol Chem 291:14896–14903. https://doi.org/10.1074/jbc.R116.734780

Article  Google Scholar 

Talevi A, Carrillo C, Comini M (2019) The thiol-polyamine metabolism of Trypanosoma cruzi: molecular targets and drug repurposing strategies. Curr Med Chem 26:6614–6635. https://doi.org/10.2174/0929867325666180926151059

Article  Google Scholar 

Carrillo C, Cejas S, González NS, Algranati ID (1999) Trypanosoma cruzi epimastigotes lack ornithine decarboxylase but can express a foreign gene encoding this enzyme. FEBS Lett 454:192–196. https://doi.org/10.1016/s0014-5793(99)00804-2

Article  Google Scholar 

Alberca LN, Sbaraglini ML, Morales JF et al (2018) Cascade ligand- and structure-based virtual screening to identify new trypanocidal compounds inhibiting putrescine uptake. Front Cell Infect Microbiol 8:173. https://doi.org/10.3389/fcimb.2018.00173

Article  Google Scholar 

Soysa R, Venselaar H, Poston J et al (2013) Structural model of a putrescine-cadaverine permease from Trypanosoma cruzi predicts residues vital for transport and ligand binding. Biochem J 452:423–432. https://doi.org/10.1042/BJ20130350

Article  Google Scholar 

Dietrich RC, Alberca LN, Ruiz MD et al (2018) Identification of cisapride as new inhibitor of putrescine uptake in Trypanosoma cruzi by combined ligand- and structure-based virtual screening. Eur J Med Chem 149:22–29. https://doi.org/10.1016/j.ejmech.2018.02.006

Article  Google Scholar 

Reigada C, Valera-Vera EA, Sayé M et al (2017) Trypanocidal effect of isotretinoin through the inhibition of polyamine and amino acid transporters in Trypanosoma cruzi. PLoS Negl Trop Dis 11:e0005472. https://doi.org/10.1371/journal.pntd.0005472

Article  Google Scholar 

Kowalczyk L, Ratera M, Paladino A et al (2011) Molecular basis of substrate-induced permeation by an amino acid antiporter. Proc Natl Acad Sci 108:3935–3940. https://doi.org/10.1073/pnas.1018081108

Article  Google Scholar 

Song Y, DiMaio F, Wang RY-R et al (2013) High-resolution comparative modeling with RosettaCM. Structure 21:1735–1742. https://doi.org/10.1016/j.str.2013.08.005

Article  Google Scholar 

Remmert M, Biegert A, Hauser A, Söding J (2012) HHblits: lightning-fast iterative protein sequence searching by HMM-HMM alignment. Nat Methods 9:173–175. https://doi.org/10.1038/nmeth.1818

Article  Google Scholar 

Larsson P, Wallner B, Lindahl E, Elofsson A (2008) Using multiple templates to improve quality of homology models in automated homology modeling. Protein Sci Publ Protein Soc 17:990–1002. https://doi.org/10.1110/ps.073344908

Article  Google Scholar 

Meier A, Söding J (2015) Automatic prediction of protein 3D structures by probabilistic multi-template homology modeling. PLoS Comput Biol. https://doi.org/10.1371/journal.pcbi.1004343

Article  Google Scholar 

Case DA, Cheatham TE III, Darden T et al (2005) The amber biomolecular simulation programs. J Comput Chem 26:1668–1688. https://doi.org/10.1002/jcc.20290

Article  Google Scholar 

Salomon-Ferrer R, Case DA, Walker RC (2013) An overview of the amber biomolecular simulation package. WIREs Comput Mol Sci 3:198–210. https://doi.org/10.1002/wcms.1121

Article  Google Scholar 

Tian C, Kasavajhala K, Belfon KAA et al (2020) ff19SB: amino-acid-specific protein backbone parameters trained against quantum mechanics energy surfaces in solution. J Chem Theory Comput 16:528–552. https://doi.org/10.1021/acs.jctc.9b00591

Article  Google Scholar 

Dolinsky TJ, Nielsen JE, McCammon JA, Baker NA (2004) PDB2PQR: an automated pipeline for the setup of Poisson–Boltzmann electrostatics calculations. Nucleic Acids Res 32:W665–W667. https://doi.org/10.1093/nar/gkh381

Article  Google Scholar 

Jo S, Kim T, Iyer VG, Im W (2008) CHARMM-GUI: a web-based graphical user interface for CHARMM. J Comput Chem 29:1859–1865. https://doi.org/10.1002/jcc.20945

Article  Google Scholar 

Wu EL, Cheng X, Jo S et al (2014) CHARMM-GUI membrane Builder toward realistic biological membrane simulations. J Comput Chem 35:1997–2004. https://doi.org/10.1002/jcc.23702

Article  Google Scholar 

Hopkins CW, Le Grand S, Walker RC, Roitberg AE (2015) Long-time-step molecular dynamics through hydrogen mass repartitioning. J Chem Theory Comput 11:1864–1874. https://doi.org/10.1021/ct5010406

Article  Google Scholar 

Alberca LN, Sbaraglini ML, Balcazar D et al (2016) Discovery of novel polyamine analogs with anti-protozoal activity by computer guided drug repositioning. J Comput Aided Mol Des 30:305–321. https://doi.org/10.1007/s10822-016-9903-6

Article  Google Scholar 

Díaz MV, Miranda MR, Campos-Estrada C et al (2014) Pentamidine exerts in vitro and in vivo anti Trypanosoma cruzi activity and inhibits the polyamine transport in Trypanosoma cruzi. Acta Trop 134:1–9. https://doi.org/10.1016/j.actatropica.2014.02.012

Article  Google Scholar 

Reigada C, Sayé M, Phanstiel O et al (2019) Identification of Trypanosoma cruzi polyamine transport inhibitors by computational drug repurposing. Front Med 6:256. https://doi.org/10.3389/fmed.2019.00256

Article  Google Scholar 

Reigada C, Phanstiel O, Miranda MR, Pereira CA (2018) Targeting polyamine transport in Trypanosoma cruzi. Eur J Med Chem 147:1–6. https://doi.org/10.1016/j.ejmech.2018.01.083

Article  Google Scholar 

Hasne MP, Coppens I, Soysa R, Ullman B (2010) A high-affinity putrescine-cadaverine transporter from Trypanosoma cruzi. Mol Microbiol 76:78–91. https://doi.org/10.1111/j.1365-2958.2010.07081.x

Article  Google Scholar 

Alhossary A, Handoko SD, Mu Y, Kwoh C-K (2015) Fast, accurate, and reliable molecular docking with QuickVina 2. Bioinformatics 31:2214–2216. https://doi.org/10.1093/bioinformatics/btv082

Article  Google Scholar 

Santos-Martins D, Solis-Vasquez L, Tillack AF, Sanner MF, Koch A, Forli S (2021) Accelerating AutoDock4 with GPUs and gradient-based local search. J Chem Theory Comput 17(2):1060–1073. https://doi.org/10.1021/acs.jctc.0c01006

Pettersen EF, Goddard TD, Huang CC et al (2004) UCSF Chimera–a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612. https://doi.org/10.1002/jcc.20084

Article  Google Scholar 

Koes DR, Baumgartner MP, Camacho CJ (2013) Lessons learned in empirical scoring with smina from the CSAR 2011 Benchmarking Exercise. J Chem Inf Model 53:1893–1904. https://doi.org/10.1021/ci300604z

Article  Google Scholar 

Fawcett T (2006) An introduction to ROC analysis. Pattern Recognit Lett 27:861–874. https://doi.org/10.1016/j.patrec.2005.10.010

Article  Google Scholar 

Wang C, Zhang Y (2017) Improving scoring-docking-screening powers of protein-ligand scoring functions using random forest. J Comput Chem 38:169–177. https://doi.org/10.1002/jcc.24667

Article  Google Scholar 

Birkholtz L-M, Williams M, Niemand J et al (2011) Polyamine homoeostasis as a drug target in pathogenic protozoa: peculiarities and possibilities. Biochem J 438:229–244. https://doi.org/10.1042/BJ20110362

Article  Google Scholar 

Borges MN, Messeder JC, Figueroa-Villar JD (2004) Synthesis, anti-trypanosoma cruzi activity and micelle interaction studies of bisguanylhydrazones analogous to pentamidine. Eur J Med Chem 39:925–929. https://doi.org/10.1016/j.ejmech.2004.07.001

Article  Google Scholar 

Braga SFP, Alves ÉVP, Ferreira RS et al (2014) Synthesis and evaluation of the antiparasitic activity of bis-(arylmethylidene) cycloalkanones. Eur J Med Chem 71:282–289. https://doi.org/10.1016/j.ejmech.2013.11.011

Article  Google Scholar 

da Silva CF, da Silva PB, Batista MM et al (2010) The biological in vitro effect and selectivity of aromatic dicationic compounds on Trypanosoma cruzi. Mem Inst Oswaldo Cruz 105:239–245. https://doi.org/10.1590/s0074-02762010000300001

Article  Google Scholar 

da Silva CF, Batista MM, da Batista D et al (2008) In vitro and in vivo studies of the trypanocidal activity of a diarylthiophene diamidine against Trypanosoma cruzi. Antimicrob Agents Chemother 52:3307–3314. https://doi.org/10.1128/AAC.00038-08

Article  Google Scholar 

Daliry A, Pires MQ, Silva CF et al (2011) The Trypanocidal activity of Amidine Compounds does not correlate with their binding Affinity to Trypanosoma cruzi kinetoplast DNA▿. Antimicrob Agents Chemother 55:4765–4773. https://doi.org/10.1128/AAC.00229-11

Article  Google Scholar 

Daliry A, Da Silva PB, Da Silva CF et al (2009) In vitro analyses of the effect of aromatic diamidines upon Trypanosoma cruzi. J Antimicrob Chemother 64:747–750. https://doi.org/10.1093/jac/dkp290

Article  Google Scholar 

De Souza EM, da Silva PB, Nefertiti ASG et al (2011) Trypanocidal activity and selectivity in vitro of aromatic amidine compounds upon bloodstream and intracellular forms of Trypanosoma cruzi. Exp Parasitol 127:429–435. https://doi.org/10.1016/j.exppara.2010.10.010

Article  Google Scholar 

González J (2007) Synthesis and antiparasitic evaluation of bis-2,5-[4-guanidinophenyl]thiophenes. Eur J Med Chem. https://doi.org/10.1016/j.ejmech.2006.11.006

Article  Google Scholar 

Klenke B, Stewart M, Barrett MP et al (2001) Synthesis and biological evaluation of s-Triazine substituted polyamines as potential new anti-trypanosomal drugs. J Med Chem 44:3440–3452. https://doi.org/10.1021/jm010854+

Article  Google Scholar 

Liew LPP, Kaiser M, Copp BR (2013) Discovery and preliminary structure-activity relationship analysis of 1,14-sperminediphenylacetamides as potent and selective antimalarial lead compounds. Bioorg Med Chem Lett 23:452–454. https://doi.org/10.1016/j.bmcl.2012.11.072

Article  Google Scholar 

Lizzi F, Veronesi G, Belluti F et al (2012) Conjugation of quinones with natural polyamines: toward an expanded antitrypanosomatid profile. J Med Chem 55:10490–10500. https://doi.org/10.1021/jm301112z

Article  Google Scholar 

Majumder S, Kierszenbaum F (1993) Inhibition of host cell invasion and intracellular replication of Trypanosoma cruzi by N,N’-bis(benzyl)-substituted polyamine analogs. Antimicrob Agents Chemother 37:2235–2238. https://doi.org/10.1128/AAC.37.10.2235

Article  Google Scholar 

Menezes D, Valentim C, Oliveira MF, Vannier-Santos MA (2006) Putrescine analogue cytotoxicity against Trypanosoma cruzi. Parasitol Res 98:99–105. https://doi.org/10.1007/s00436-005-0010-1

Article  Google Scholar 

Pacheco MG, de O CF, de Souza EM et al (2009) Trypanosoma cruzi: activity of heterocyclic cationic molecules in vitro. Exp Parasitol 123:73–80. https://doi.org/10.1016/j.exppara.2009.06.004

Artic